Phenoxycarbamates

ABSTRACT

AND PHARMACEUTICALLY ACCEPTABLE, NON-TOXIC ACID ADDITION SALTS THEREOF, WHEREIN R&#39;&#39; is an isopropyl or tertiarybutyl radical; Z is a member selected from the group consisting of -OR&#39;&#39;&#39;&#39;, -SR&#39;&#39;&#39;&#39;, and -NHCOOR&#39;&#39;&#39;&#39;, R&#39;&#39;&#39;&#39; being a straight or branched lower alkyl radical having 1 to 3 carbon atoms; and n is 1, 2, or 3, are disclosed as are methods for their preparation. Pharmaceutical preparations are prepared whose active ingredients include at least one of the newly discovered phenoxy-hydroxypropylamine compounds. Therapeutically effective doses of these preparations selectively block the Beta -receptors of the heart making them useful in treating heart diseases in animals including humans.   Para-substituted phenoxy-hydroxypropylamines having the general formula

United States Patent Brandstrom et al.

l PHENOXYCARBAMATES [761 Inventors: Arne Elof Brandstrom,

Mattssonsgatan 13 B, 5-415 ()6 Goteborg; Per Arvid Emil Carlsson, TorildWulffsgatan 50, S-413 19 Goteborg; Stig Ake lngemar Carlsson,Honekullavagen 43F, 5-435 00 Molnlycke; Hans Rudolf Corrodi,Hogbergsgatan 1, 8-151 33 Sodertalje; Lars Ek, Mansagarden PL 5102, $43034 Onsala; Bengt Arne Hjalmar Ablad, Folke Bernadottes gata 2, S-411 28Goteborg, all of Sweden- 22 Filed: Mar. 19,1973

[21] Appl. N0.:342,749

Related US. Application Data [63] (ontinuation-in-part of Ser. No.115,851, Feb. 16,

1971, abandoned.

[30] Foreign Application Priority Data Feb. 18 1970 Sweden 2050/70 [52]US. Cl 260/471 C, 260/570.7, 424/300, 424/330 [51] Int. Cl. C07c 125/06Field of Search 260/471 C [56] References Cited UNITED STATES PATENTS3.712927 l/l973 l-lowe et al 260/471 C 1 1 Mar. 25, 1975 PrinmryI:.\'umim"r-Lorraine A. Weinhergcr Assistant Examiner-L. A. ThzlxtonAttorney, Agent, or FirmBrumbaugh. Graves. Donohue & Raymond [57]ABSTRACT Para-substituted phenoxy-hydroxypropylamines having the generalformula (CH Z and pharmaceutically acceptable, non-toxic acid additionsalts thereof, wherein R is an isopropyl or tertiarybutyl radical; Z isa member selected from the group consisting of OR", SR, and -NH- COOR,R" being a straight or branched lower alkyl radical having 1 to 3 carbonatoms; and n is 1, 2, or 3, are disclosed as are methods for theirpreparation. Pharmaceutical preparations are prepared whose activeingredients include at least one of the newly discoveredphenoxy-hydroxypropylamine compounds. Therapeutically effective doses ofthese preparations selectively block the ,B-receptors of the heartmaking them useful in treating heart diseases in animals includinghumans.

11 Claims, N0 Drawings PHENOXYCARBAMATES This is a continuation-in-partof our copending application Ser. No. 115,851 filed Feb. 16, 1971 nowabandoned.

The present invention relates to phenoxyhydroxypropylamines and, inparticular, to parasubstituted phenoxyhydroxypropylamines and methodsfor their preparation. The invention also relates to the preparation ofpharmaceutical preparations containing such para-substitutedphenoxyhydroxypropylamines as active ingredients and to a method for thepharmacological use of such compounds.

B-Rcceptor blocking agents such as propranolol,

-CH2-CH-CH2-NHCH(CH3)2 alprenoioi and oxprenolol,

-'o-carcreca (III) have been shown to possess good therapeutic effectsin treating heart diseases and vascular diseases, such as anginapectoris, hypertension, vasoregulatoric neurasteni and certain forms ofarrythmia.

Certain disadvantages have been experienced in the therapeutic use ofthese compounds since they block not only the B-receptors of the heart,which leads to the therapeutic effect, but also the ,B-receptors inblood vessels and bronchi. The latter blocking activity results inundesired side effects with some patients having manifest or latentasthma. Blocking of the ,B-receptors in the bronchi may in such caseslead to broncho-spasm and attacks of asthma. For this reason, asthma isa contraindication for heart disease treatment with the knownB-receptorblocking substances such as propanolol. alprenolol, andoxprenolol. The receptor blocking effect on blood vessels of thesecompounds causes adrenaline, which is released from the marrow of thesuprarenal glands, to have a pure pressor effect instead of the balancedpressor-depressor effect normally maintained by adrenaline flow.

Accordingly, the main object of the invention is to provide newpara-substituted phenoxyhydroxypropylamine compounds having variablepharmacological properties which can be used in the treatment of heartdisease.

Another object of this invention is to provide new compounds which havea therapeutic effect in treating heart diseases without inducingcomplications due to B-blockade in bronchi and in blood vessels.

These and other closely related purposes of the present invention areachieved by administering parasubstituted phenoxyhydroxypropylaminederivatives characterized by the following general formula:

o-cii -tlia-ca naa' (ca z and pharmaceutically acceptable, non-toxicacid addition salts thereof, wherein R is an isopropyl or tertiarybutylradical; Z is a member selected from the group consisting essentially of-OR, --SR, and --NH- COOR, R" being a straight or branched chain loweralkyl radical having 1 to 3 carbon atoms; and n is l, 2, or 3.

The para-substituted phenoxy-hydroxypropylamine compounds discoveredcontain an asymmetric carbon atom and, therefore, they exist asoptically active forms. The racemic mixture can, of course, be resolvedinto its optical antipodes by well known methods, such as by usingoptically active acids such as tartaric acid, camphor-lO-sulphonic acid,dibenzoyl tartaric acid, and the like. Some examples of compoundsaccording to the invention are: l-isopropylamino-3-[p-(B-methoxyethyl)-phenoxy]-propanol- 2;isopropylamino-3-[p-(B-ethoxyethyU-phenoxy]- propanol-Z;l-isopropylamino-3-[p-(ethoxymethyl)- phenoxy -propanol-2;l-isopropylamino-3-[ p-( ymethoxypropyl)-phenoxy]-propanol-2;isopropylamino-3-[p-(B-methylmercaptoethyl)- phenoxy1-propanol-2; andl-isopropylamino-3-[p-(B-methoxycarbonylamidoethyl)-phenoxy]-propanol-2.

l-lsopropylamino-3-[p-(B-methoxyethyl)-phenoxy]- propanol-Z andl-isopropylamino-3-[p-(B- methoxycarbonylamidoethyl)-phenoxy]-propanol-2are preferred both as racemates as well as in the form of theirpharmacologically and optically active isomers.

The para-substituted phenoxy-hydroxypropylamines of Formula lV may beprepared by several methods which are defined as follows:

A. Reacting a compound of the formula in which formulas R is anisopropyl or tertiary-butyl radical; Z is a member selected from thegroup consisting of OR". SR, and -NHCOOR", R being a straight orbranched lower alkyl radical having 1 to 3 carbon atoms; and n is l, 2,r 3. Q in Formula V represents t -c -cH or CHOHCH -X, wherein X is ahalogen atom, preferably chlorine.

B. Reacting a compound of Formula V with an amine of the formula H NR'wherein :1, Z, R, and Q have the same meaning designated above in A.

C. Alkylating a compound of the formula -CH -CH-CI:i -NH (CH Zreductively by using hydrogen and acetone to form a compound of theformula CH OCH -CH-CH NH-CH (VIII) in which formulas n. and Z have thesame meaning as designated in A.

D. Alkylating a compound of the formula (ca z by reacting it with acompound of the formula X-- CH[CH to form compounds of formula Vlll,wherein M, Z, R, and X have the same meaning as des- 5 ignated in A.

E. Hydrolysis of a compound of the formula (CH Z wherein M, Z, and Rhave the same meaning as in A and R is a group which can be removedhydrolytically, preferably an acyl or a tetrahydropyranyl group.

F. Hydrolysis of a compound of the formula (CH Z using a strong alkalior strong acid, wherein n, Z, and

\ OH R' (XII) (cn z wherein n, Z, and R have the same meaning as in Aand R is a protecting group such as benzyl, acetyl or carbobenzoxygroup.

1. Reacting a phenolate of the formula (XIV) (CH Z with a compound ofthe formula QCH NHR (cn o z preferably by using a complex alkali metalhydride,

wherein n, Z, and R have the same meaning as in A and Y represents-CHOH-CO or CO-CH K. Hydrolysis of a compound of the formula wherein n,Z, and R have the same meaning as in A, and R is a lower alkyl, aralkyl,or aryl group, preferably a phenyl group.

If desired, the racemates obtained by any of the methods A-K may beresolved into their optically active antipodes. When a pharmaceuticallyacceptable, non-toxic acid addition salt is desired, the compound formedis reacted with a suitable acid.

The method of preparation A is preferably performed in a high boiling,inert, organic solvent, such as 1,2,3,4-tetrahydronaphthalene,decahydronaphthalene, benzonitrile, paraffin oil or chlorinated,aromatic organic solvents; alternatively, the reaction may be carriedout in the molten state at a temperature of C. 220C, preferably 180C.200C.

The properties of the novel para-substituted phenoxyhydroxypropylamines,particularly their selectivity in blocking the fi-receptors of theheart, make them useful in treating heart diseases in animals includinghumans. In clinical practice the compounds of the present invention willnormallyy be administered orally, rectally or by injection, in the formof pharmaceutical preparations comprising as the active ingredi ent atleast one ofthe compounds encompassed by Formula IV as defined herein.The active ingredients may be used either as a free base or as apharmaceutically acceptable non-toxic, acid addition salt, for example,the hydrochloride, lactate, acetate, sulfamate, and the like, inassociation with a pharmaceutically acceptable carrier. Accordingly,terms relating to the novel compounds of this invention whethergenerically or specifi cally are intended to include both the freeamine'base and the acid addition salts of the free base, unless thecontext in which such terms are used, particularly in the examples,would be inconsistent withthe broad concept. The carrier may be a solid,semi-solid or liquid diluent or capsule.

The pharmaceutical preparations are a further aspect of this invention.Usually the active substance will constitute between 0.1 and 95% byweight of the preparation, more specifically between 0.5 and 2 0%byweight for preparation intended for injection and between 0.2 and 50% byweight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of theinvention in the form of dosage units for oral application, the selectedcompound may be mixed with a solid pulverulent carrier, for example.lactose, saccharose, sorbitol, mannitol, starches such as potato starch,corn starch or amylopectin, cellulose derivatives, or gelatin, and alubricant such as magnesium stearate, calcium stearate, polyethyleneglycol waxes, and the like, and then compressed to form tablets. lfcoated tablets are required, the cores, prepared as described above, maybe coated with a concentrated sugar solution which may contain, forexample, gum arabic, gelatin, talcum, titanium dioxide, and the like.Alternatively, the tablet can be coated with a lacquer dissolved in areadily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatin capsules (pearlshaped closedcapsules) consisting of gelatin and, for example, glycerol or similarclosed capsules, the active substance may be admixed with a vegetableoil. Hard gelatin capsules may contain granulates of the activesubstance in combination with solid, pulverulent carriers such aslactose. saccharose, sorbitol, mannitol, starches (e.g., potato starch,corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal application can be prepared in the form ofsuppositories comprising the active substance in admixture with aneutral fatty base, or gelatin rectal capsules comprising the activesubstance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing from about 0.2 to about20% by weight of the active substance according to Formula IV, thebalance being sugar and a mixture of ethanol, water, glycerol, andpropylene glycol. Optionally, such liquid preparations may containcoloring agents, flavoring agents, saccharine and carboxymethylcelluloseas a thickening agent.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance preferably in a concentration of from about 0.5 toabout 10% by weight. These solutions may also contain stabilizing agentsand/or buffering agents and may conveniently be provided in variousdosage unit ampoules.

The following examples illustrate the principles and practices of theinvention and are not intended to limit its scope in any way. Allpercentages are by weight unless otherwise indicated.

EXAMPLE I l,2-epoxy-3-[p-(B-methoxyethyl)-phenoxy]-propane (16.7 g wasdissolved in 50 ml isopropanol and mixed with ml isopropylamine. Themixture was heated in an autoclave on boiling water-bath overnight,whereafter it was evaporated and the remainder dissolved in 2 N HCL. Thesolution was extracted first with ether and thereafter with methylenechloride. After evaporating the methylene chloride. phase, thehydrochloride of 1- isopropylamino-3-[p-(,B-methoxyethyl)-phenoxy]-propanol-Z was obtained which, after recrystallization from ethylacetate, weighed 10.4 g. Melting point 83C. Equiv. weight: found 304.0,calculated 303.8. The starting material l,2-epoxy-3-[p-(B-methoxyethyl)-phenoxy]-propane was obtained from p-(B- methoxyethyl)-phenol which wasreacted with epichlorohydrine whereafter the reaction product wasdistilled at 1 18128C. at a pressure of 0.35 mm Hg.

According to the method described in Example I, the following compoundswere similarly prepared as hydrochlorides.

EXAMPLE II 1 -isopropylamino-3-[ p-(B-ethoxyethyl )-phenoxy]- propanol2.Melting point 102C. Equiv. weight: found 323.0, calculated 317.8.

EXAMPLE III 1 isopropylamino-3-(p-ethoxymethyl-phenoxy)- propanol-2.Melting point 94C. Equiv. weight: found 304.0, calculated 303.8.

EXAMPLE V l-Isopropylamino-3-[p-(B-methylmercaptoethyl)-phenoxyl-propanol-Z in base form was prepared in accordance with ExampleI with the exception that no reaction with hydrochloric acid took place.Melting point 60C. Equivalent weight: found 284, calculated 283.

EXAMPLE VI l-Isopropylamino-3-l p-(y-methoxypropyl phenoxyl-propanol-Z,melting point 89C (hydrochloride) was prepared. The starting materialp-(y-' methoxypropyl)-phenyl-glycidyl ether has a boiling point at102-112C and 0.03 mm Hg. Equivalent weight: found 314.0, calculated317.8.

EXAMPLE VII l-isopropylamino-3-[p-(B-methoxycarbonylamidocthyl)-phenoxy]-propanol-2. Melting point 106C.Equiv. weight: found 349, calculated 347.

EXAMPLE VIII 1-isopropylamino-3-[p-(B-ethoxycarbonylamidoethyl)-phenoxy]-propanol-2. Melting point 120C.Equiv. weight: found 364, calculated 361.

The para-substituted phenylglycidyl ethers used in Examples 11 VIII wereobtained from the corresponding phenols and epichlorohydrin according toExample I. These glycidyl ethers were used without isolation until thelast step.

EXAMPLE IX (Illustrating Method B) y I 5 g of p-(B-methoxyethyl)-phenol,ml of epichlorhydrin and 0.5 ml of vpiperidine were heated on a boilingwater bath for 10 hours. The mixture was thereafter evaporated atreduced pressure and the residue was dissolved in chloroform and wasthereupon extracted with hydrochloric acid. The chloroform phase waswashed with water, dried'and evaporated at reduced pressure. The residueconsisting of 3-[p-(B- methoxyethyl)-phenoxy]-l-chloropropanol-2 wasdissolved in 20 ml ofisopropyl alcohol to which was added 10 ml ofisopropylamine and the mixture was heated in an autoclave on a waterbath with boiling water for 10 hours. Thereafter the mixture wasevaporated and the residue was shaken with a mixture of 2/N NaOH andether. The ether phase was dried and evaporated at reduced pressure. Theresidue so obtained crystallized from petroleum ether and there was thusobtained 1- isopropylamino-3-[p-(B-methoxyethyl)- phenoxy]-propano1-2,which was converted to the hydrochloride in accordance with Example I.The melting point of the hydrochloride was 83C.

EXAMPLE X (Illustrating Method C) A solution of 20 g ofp-(B-methoxyethyl)-phenyl glycidyl ether in 200 ml of ethanol saturatedwith ammonia was heated in an autoclave on a water bath with boilingwater for 4 hours. The mixture was thereupon evaporated and the residuewas dissolved in ethyl acetate whereupon gaseous HCl was introduced intothe solution. The hydrochloride of the amine, which then crystallized,was removed by filtration and 5 g was dissolved in 50 ml of methanol and10 ml of acetone. The solution was cooled to C and g of sodiumborohydride was added in portions during 1 hour. Then 2.5 ml of acetoneand 0.8 g of sodium borohydride were added and the solution was kept atroom temperature for 1 hour whereupon 150 ml of H 0 was added. Themixture was extracted with ether whereupon the ether phase was driedover potassium carbonate and evaporated. The residue was transformed tothe hydrochloride by dissolving the base in ethyl acetate andintroducing gaseous HCI into the solution. In this way the hydrochlorideof l-isopropylamino-3-[p-(B- methoxyethyl)-phenoxy]-propanol-2 wasobtained having a melting point of 83C.

EXAMPLE XI (Illustrating Method D) A solution of g ofp-(B-ethoxyethyU-phenyl glycidyl ether in 100 ml of ethanol wassaturated with ammonia whereupon the mixture was heated upon a waterbath containing boiling water for 4 hours. Thereafter the reactionmixture was evaporated and the residue dissolved in ethyl acetate. HClin gaseous form was introduced causing the amine hydrochloride tocrystallize. The crystals were removed by filtration and dissolved in 70ml of ethanol whereupon l0 ml of isopropylbromide and 12 g of potassiumcarbonate was added. The mixture was heated in an autoclave at [20C forl0 hours whereupon the ethanol was removed by evaporation. To theresidue was added 100 ml of 2/N HCl and 100 ml of ether. The water phasewas separated and alkalized with 2/N NaOH and thereupon extracted withethyl acetate. The ethyl acetate phase was dried by means of potassiumcarbonate whereupon gaseous HCI was introduced. This causedcrystallization of the hydrochloride which was separated by filtrationand recrystallized from methylethylketone. There was thus obtained thehydrochloride of l-isopropylamino-3-[p-(B-ethoxyethyl)-phenoxy]-propanol-Z having a melting point of 102C.

EXAMPLE XII (Illustrating Method E) A solution of 8 g of3-[p-(B-ethoxyethyl)-phenoxy]- l-chloropropanol-Z (prepared for instanceaccording to method B) in 15 ml of dihydropyran was mixed with a smallamount of p-toluene sulphonic acid. This caused an increase of thetemperature to 50C and after having been kept at this temperature for 30minutes the mixture was dissolved in 100 ml of ethanol whereupon 10 mlof isopropylamine was added. The reaction was heated in an autoclave for10 hours on steam bath and was thereafter evaporated. The residue wasdissolved in ethyl acetate to which was added oxalic acid and wasthereupon diluted with ether. The crystallized oxalate was separated andrecrystallized from ethanol/ether. To the oxalate was added 50 ml of 2/NHCI and the mixture was heated on water bath for 15 minutes. Aftercooling the mixture was alkalized by addition of NaOH and the base wasextracted with ether. The ether phase was dried and evaporatedwhereafter the residue was dissolved in ethyl acetate followed byintroduction of gaseous HCI. The precipitate thus obtained wasrecrystallized from methylethylketone which gave the hydrochloride oflisopropylamino-3-lp-(B-ethoxyethyl)-phenoxy]- propanol-Z having amelting point of 103C.

EXAMPLE XIII (Illustrating Method F) 5.5 g of3-isopropyl-5-[p-(B-methoxyethyl)-phen0xymethyl]-oxazolidinone-2 wasdissolved in 60 ml ofethanol to which was added a solution of 9 g of KOHin IS ml of H 0. The mixture was refluxed, was thereupon evaporated andthe residue dissolved in 2/N HCI and extracted with ether. The waterphase was alkalized with NaOH and extracted with ether. After drying bymeans of potassium carbonate, gaseous HCl was introduced, causing thehydrochloride of l-isopropylamino-3[p-(B-methoxyethyl)-phenoxyJ-propanol-2 to crystallize. Thehydrochloride gave after recrystallization from methylethyl ketone. amelting point of 83C.

EXAMPLE XIV (Illustrating Method A and G) 4.5 g ofp-(B-ethoxyethyU-phenyl glycidyl ether was dissolved in 50 ml oftetralin to which was added 5.7 g of N,N-diisopropylurea and 20 g oflithium hydroxide whereupon the mixture was heated at 200C for 3 hours.The reaction mixture was after cooling diluted with 50 ml ofether andshaken with ml of 2/N HCl. The water phase was extracted with ether andthereupon alkalized by addition of NaOH and was finally shaken withether. The ether phase was washed with water, dried and evaporated. Theresidue was dissolved in ethyl acetate and the hydrochlorideprecipitated by addition of asolution of gaseous HCI in ether. Thehydrochloride of l-isopropylamino-3-l p-( B-ethoxyethyl)-phenoxy]-propanol-2 with a melting point of 102C wasobtained after recrystallization from methylethyl ketone.

EXAMPLE XV (Illustrating Method H and I) 0.92 g of Na was dissolved in50 ml of alcohol and to the solution was added 6.1 g ofp-(B-methoxyethyl)- phenol 9.6 g of 3-(N-benzyl-N-isopropylamino)-lchloropropanol-Z. The mixture was heated in an autoclave on steam bathovernight and was thereupon filtered and evaporated to dryness. To theresidue was added 100 ml of 2/N HCI and the mixture was extracted withether whereupon the water phase was alkalized by addition of NaOH andthereupon shaken with either. The ether phase was dried and evaporatedand the residue obtained dissolved in 200 ml of alcohol and neutralizedwith concentrated HCI. To this solution was added 0.5 g of Pd/C catalystand the reaction mixture was hydrogenated at atmospheric pressure untilthe calculated amount of H had been consumed.

After filtering, the reaction mixture was evaporated to dryness and theresidue thereupon recrystallized from EXAMPLE XVI (Illustrating Method.1)

15.2 g of p-(,B-methoxyethyU-phenol was dissolved in a solution of 4.6 gof Na in 100 ml of ethanol. To the solution was added 12.5 g of2-hydroxy-3- chloropropionic acid and the mixture was refluxed for 3hours. The mixture was thereupon evaporated and to the residue was added100 ml of 2/N HCl and the resulting mixture was thereupon extracted withbenzene. The benzene phase was shaken with sodium bicarbonate solutionwhich was thereupon acidified by addition of HCl followed by anextraction with benzene. After evaporation2-hydroxy-3-lp-(methoxyethybphenoxylpropionic acid was obtained whichwas coverted to N- isopropylamide by dissolving the acid intetrahydrofuran followed by an addition of isopropylamine anddicyclohexyl-dicyclohexyl-dicarbodiimide and heating the reactionmixture at 40C for 5 hours. To the solution, after filtering, was added5 g of lithium aluminum hydride and the mixture was refluxed overnight.After the application of conventional separation methods,l-isopropylamino-3-[p-(B-methoxyethyl)-phenoxy]- propanol-Z wasobtained, which, after conversion to the hydrochloride, had a meltingpoint of 82C.

EXAMPLE XVIl (Illustrating Method K) To 5 g ofN-isopropyl-N-[3-/p-(B-methoxyethyl)- phenoxy-Z-hydroxypropyl] carbamicacid ethyl ester was added 25 ml of 2/N HCl and the mixture was heatedon water bath for 2hours. After cooling, the mixture was extracted withether and the water phase was alkalized by addition of NaOH, followed byan extraction with ether. After drying and evaporation andrecrystallization from petroleum ether, 1-isopropylamino-3-[p-(B-methoxyethyl)-phenoxy]- propanol-Z was obtainedhaving a melting point of 83C, (hydrochloride).

EXAMPLE Vlll (Method other than A-K)l-lsopropylamino-3-[p-(y-aminopropyl)-phenoxy]- propanol-Zdi-HCl (3.4 g)was dissolved in ml H O. Sodium bicarbonate (2.6 g) was added to thesolution and after a few minutes while stirring, 1.0 g of methylchloroformate was added. The mixture was stirred overnight at roomtemperature, followed by extraction with methylene dichloride. Themethylene dichloride phase was dried with K CO filtered and evaporated.In this way the base form ofl-isopropylamino-3-[p-('ymethoxycarbonylamidopropyl)-phenoxy]-propanol-2-was obtained (m.p.=72C). Equivalent weight: Found 329; Calculated 324.

The starting material,l-isopropylamino-3-[p-(yaminopropyl)-phenoxy]-propanol-2, was preparedin the following manner: p-(B-cyanoethyUphenol (100.9 g), 149.1 gepichlorohydrin, 226 g K CO and 700 ml acetonitrile were mixed andrefluxed while stirring overnight.

After filtration, the filtrate, was evaporated in vacuo. The residue (115 g) was dissolved in 300 ml of isopropanol; 300 ml of isopropylaminewas added, whereupon the mixture was refluxed for 3 hours. Afterevaporation in vacuo 138.5 g of an oil was obtained. 8.5 g of this oilwas dissolved in 500 ml of ethanol (99%) and 8.5 ml of conc. HCl wasadded, followed by hydrogenation at 3.5 atm. (0.5 g. Pd/C as acatalyzing agent) until the calculated amount of hydrogen was consumed.After filtration, evaporation and recrystallization from alcohol, thedihydrochloride of l-isopropylamino-3-[p-('y-aminopropyl)-phenoxy]-propanol-2 (mp. 180C) was obtained.

EXAMPLE XIX According to the method described in Example XVlll thecompound l-tert.-butylamino-3[p-(B-methoxycarbonylamidoethyl)-phenoxy]-propanol-2 was prepared (m.p.=92C inbase form; Equivalent weight: found 325; calculated 324). The compound1- tert.-butylamino-3-[p-(fi-aminoethyl)-phenoxy]- propanol-2-di-HC1(m.p.=l92C) was used as starting material. This latter compound wasprepared according to the method described in Example XVlIl usingpcyanomethylphenol and tert.-butylamine as starting materials.

PHARMACOLOGICAL EVALUATION Compounds prepared according to the exampleswere evaluated for intrinsic activity and blocking effect on heart rateand peripheral vasodilator response to isoprenaline in the cat. Theacute LD in mice was evaluated. Alprenolol was used as a referencesubstance.

Cats weighting between 1.8 and 2.8 kg were anaesthetized with 30 mg/kgpentobarbital sodium, intraperitoneally. The cats had been pretreatedwith reserpine, 5 mg/kg intramuscular, about 18 hours before theexperiment. Bilateral vogotomy was performed before the start of theexperiment.

The heart rate was recorded on an Offner cardiotachometer triggered bythe EKG-complex. Means arterial blood pressure was recorded from acarotid artery. The v peripheral resistance was measured in one of thelegs of the cat in the following way: The femoral artery was opened inthe inguinal region and the leg was perfused by blood delivered througha sigma motro pump at constant rate. The flow resistance (the pressure)was recorded via a pressure transducer connected to the catheterdistally to the pump. The paw was excluded from the circulation by atight ligature lntravenously injected isoprenaline increased the heartrate and reduced the perfusion pressure. An isoprenaline dose giving 80%of the maximal chronotropic response was determined. This dose (usually0.1 ug/kg) was then repeated with 20 minute intervals. Ten minutesbefore each isoprenaline injection, the tested substances wereadministered intravenously for 2 minutes, starting with a dose of 0.01mg/kg and increasing each subsequent does four-fold. The intrinsiceffects of the test substances were determined. The dose producing 50%blockade of isoprenaline responses was evaluated from the plotted logdose-per cent blockade diagrams.

Table 1 shows the results of foregoing experiments for intrinsicstimulating activity on heart rate in cats, B-blocking activity on heartrate and peripheral vascular resistance in cats and LD afterintraperitoneal administraton in mice.

(XVIII) (CH Z TABLE I EXAMPLE XX A syrup containing 2% (weight pervolume) of active substance according to the invention was produced fromthe following ingredients:

Compounds Tested Reserpiniz'ed cat Mouse Intrinsic p-blo k dB-blockactivitv Heart rate 'ade (CH Z 96 of manual E mg/kgperi'oheral 50isoprenallne vascular 1 p (except allyl) heart rate r t' es/ g o-allyl(alprenolol) 20 0.1 0.05 100 CH OCH CH -(Ex. I) 0 0. 4 3 200 C H OCH CH(Ex. II) o 0.3 o

C H OCH -(Ex. III) 0 0. 4 6 175 CH OC-NHCH CH (Ex.VII) O 0. 19 125 C HOE-NHCH CH 0 0.3 200 (EX.VIII) The results reported in Table I, showthat the phenoxy-hydropropylamine test substances according to theinvention were 3-4 times less active than alprenolol, the standardreference, as regards blockade of the B-receptors of the heart. Theperipheral vascular heart than of the receptors in smooth muscles. Dueto this cardioselectivity, the compounds according to the invention givetherapeutic effects in treating cardiovascular diseases without risk orcomplications due to B-blockade in bronchi and blood vessels.

The following examples illustrate methods of preparing somepharmaceutical preparations according to the invention.

The sugar, saccharin and the ether salt were dissolved in 60 grams ofhot water. After cooling, the glycerol was added and a solution of theflavoring agent in ethanol was added. The mixture was then made up to avolume of milliliters with water.

The active substance in this composition may be replaced by otherpharmaceutically acceptable, nontoxic acid addition salts.

EXAMPLE XXI 15 resulting mixture was pressed into tablets (10,000)containing 25 milligrams of active substance which were suitable for useas tablets. The tablets were marked with break lines to enable a doseother than 25 milligrams or multiples thereof to be administered.

EXAMPLE XXll A granulate was prepared from l-isopropylamino-3-(ethoxymethyl'phenoxy)-propanol-2 hydrochloride (250 g), lactose (175.9g) and an alcoholic solution of polyvinyl pyrrolidone (25 g). Afterdrying, the granulate was mixed with talc (25 g), potato starch (40 g)and magnesium stearate (2.50 g) and pressed into 10,000 biconvextablets. These tablets were first coated with a alcoholic shellacsolution and then with a water solution containing saccharose (45%), gumarabic (5%), gelatin (4%) and dyestuff (0.2%). Talc and sugar powderwere used as dusting powders after the first applications. The coatingwas then finished with a 66% sugar syrup and polished with a 10%carnauba wax solution in carbon tetrachloride.

EXAMPLE XXlll l-isopropylamino-3-( p-methoxyethylphenoxy)- propanol-2hydrochloride (1g), sodium chloride (0.8 g) and ascorbic acid (0.1 g)were dissolved in sufficient distilled water to make 100 milliliters ofsolution. This solution, each milliliter of which contained 10milligrams of the active substance, was used to fill ampoules which weresterilized by heating for minutes at 120C.

Many obvious variations of the invention disclosed will suggestthemselves to those skilled in the art. Nothing in the precedingspedification is intended, however, to limit the scope of the inventionas defined by the following claims.

We claim: 1. A compound of formula OCH (l3H-CH .NHR

I (CH Z and pharmaceutically acceptable, non-toxic acid addi-.

tion salts thereof, wherein R is an isopropyl or tertiary butyl radical;Z is -NHCOOR", R being straight or branched alkyl radical having 1 to 3carbon atoms; and n is l, 2, or 3.

4. A compound according to claim 1 in optically active form, as thedextro-rotatory antipode and pharmaceutically acceptable, non-toxic acidaddition salts thereof.

5. A compound according to claim 1 wherein R is isopropyl.

6. The compound of claim 1 (i)-l-isopropylamino-3-[p-methoxycarbonylaminoethyl)-phenoxy]- propanol-Z andpharmaceutically acceptable, nontoxic acid addition salts thereof.

7. The compound of the claim 1 (-)-1-isopropylamino-3-[p-(B-methoxycarbonylaminoethylphenoxyl]-propanol-2 andpharmaceutically acceptable, non-toxic acid addition salts thereof.

8. The compound of claim 1 (+)-1-isopropylamino-3-[p-methoxycarbonylaminoethyl)-phenoxy]- propanol-2 andpharmaceutically acceptable, nontoxic acid addition salts thereof.

9. The compound of claim 1, l-isopropylamino-3-[p-('y-methoxycarbonylaminopropyl)-phenoxy]- propanol-2 andpharmaceutically acceptable, nontoxic acid addition salts thereof.

10. The compound of claim 1 wherein R'is tertiary.- butyl.

11. The compound of claim 1, l-tert.-butylamino-3-[p-(,B-methoxycarbonyluminoethyl)-phenoxy]- propanol-Zandpharmaceutically acceptable, non-toxic acid addition salts thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 1 3 73 00 DATED 3 March 25, 1975 |NV ENTOR(S) 1 Arne ElofBrandstrom et al It is certified that error appears in theab0ve-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 6, line 30, change "normallyy" to normally-;

Col. 8, line 8, change "lTertiarybutylamino" to l-Iertiaryutylamino--;

Col. 15, line 38, after "of", insert the;

Col. 16, line 3, after "being", insert a;

Col. 16, line 10, change "levo-rotatory" to according;

Col. 16, line 11, change "levo-rotary" to -levorotatory-;

Col. 16, line 23, after "3- [p" and before "methoxy" insert Col. 16,line 26, delete "the";

Col. 16, end of line 27, change "ethyl" to ethyl) Col. 16, line 28,change "phenoxyl" to -phen0xy-;

Col. 16, line 32, after "3- [p-" and before "methoxy" insert (6- Col.16, line 44, change "methoxycarbonyluminoethyl" tomethoxycarbonylaminoethyl; and

Col. 16, line 45, change "propanol-Zand" to propanol-Z and.

Signed and Scaled this twenty-fourth D ay 0f February 19 76 [SEAL] Attes t:

RUTH. C. MEX-SON C. MARSHALL DANN Arresting ()jjlter (mnmissiunvrnj'larenrs and Trademarks

1. A COMPOUND FORMULA
 2. A compound according to claim 1 in racemic formand pharmaceutically acceptable, non-toxic acid addition salts thereof.3. A compound levo-rotatory to claim 1 in optically active form, as thelevo-rotary antipode and pharmaceutically acceptable, non-toxic acidaddition salts thereof.
 4. A compound according to claim 1 in opticallyactive form, as the dextro-rotatory antipode and pharmaceuticallyacceptable, non-toxic acid addition salts thereof.
 5. A compoundaccording to claim 1 wherein R'' is isopropyl.
 6. The compound of claim1 ( + or -)-1-isopropylamino-3-(p-methoxycarbonylaminoethyl)-phenoxy)-propanol-2and pharmaceutically acceptable, non-toxic acid addition salts thereof.7. The compound of the claim 1 (-)-1-isopropylamino-3-(p-( Beta-methoxycarbonylaminoethyl-phenoxyl)-propanol-2 and pharmaceuticallyacceptable, non-toxic acid addition salts thereof.
 8. The compound ofclaim 1(+)-1-isopropylamino-3-(p-methoxycarbonylaminoethyl)-phenoxy)-propanol-2and pharmaceutically acceptable, non-toxic acid addition salts thereof.9. The compound of claim 1, 1-isopropylamino-3-(p-( gamma-methoxycarbonylaminopropyl)-phenoxy)-propanol-2 and pharmaceuticallyacceptable, non-toxic acid addition salts thereof.
 10. The compound ofclaim 1 wherein R''is tertiary.-butyl.
 11. The compound of claim 1,1-tert.-butylamino-3-(p-( Beta-methoxycarbonyluminoethyl)-phenoxy)-propanol-2and pharmaceuticallyacceptable, non-toxic acid addition salts thereof.